CHAPTER ONE

1.0 INTRODUCTION

1.1 Background of Study

Cytopathology is a branch of pathology that studies and diagnoses diseases on the cellular

level. Cytopathology is generally used on samples of free cells or tissue fragments, in contrast

to histopathology, which studies whole tissues. Cytopathology is frequently, less precisely,

called "cytology", which means "the study of cells" (Kirkpatrick, 2022).

Cytopathology is commonly used to investigate diseases involving a wide range of body

sites, often to aid in the diagnosis of cancer but also in the diagnosis of some infectious

diseases and other inflammatory conditions (Kirkpatrick, 2022).. For example, a common

application of cytopathology is the Pap smear, a screening tool used to detect precancerous

cervical lesions that may lead to cervical cancer.

Cytopathologic tests are sometimes called smear tests because the samples may be smeared

across a glass microscope slide for subsequent staining and microscopic examination.

However, cytology samples may be prepared in other ways, including cytocentrifugation.

Different types of smear tests may also be used for cancer diagnosis. In this sense, it is

termed a cytologic smear.

Liquid-based cytology is a method of preparing samples for examination in cytopathology.

The sample is collected, normally by a small brush, in the same way as for a conventional

smear test, but rather than the smear being transferred directly to a microscope slide, the

sample is deposited into a small bottle of preservative liquid. At the laboratory, the liquid is

treated to remove other elements such as mucus before a layer of cells is placed on a slide

(Liptak et al., 2012).

1.2 Statement of the problem

Cytology has limitations such as potential sample errors, subjective interpretation and the

ability to provide detailed tissue architecture information compared to histopathology.

Results depend on the quality and representativeness of the sample obtained and errors may

occur if the sample is not taken from the right location.

1.3 Limitations of the study

Liquid based cytology while offering advantages, has limitations including increased cost,

technical complexity and the potential for artefacts that may affect sample interpretation.

1.4 Aim and objectives of the study

1.4.1 Aim

The study is designed to evaluate locally prepared verse commercial liquid base cytology

transport media for cytological sample preservation analysis.

1.4.2 Specific objective

1. To access the efficacy of locally prepared transport media for cytological samples.

2. To compare the efficacy of locally prepared and commercial liquid base cytology

transport media.

1.5 Research questions

1. What is the efficacy of locally prepared transport media for cytological samples?

2. Does the efficacy of locally prepared transport media differs from commercial liquid base

cytology transport media?

1.6 Research Hypothesis

At the end of this research and testing of hypothesis, the following null hypothesis (H0)

shall either be accepted or rejected:

H0: Locally prepared transport media for cytological sample has no significant change

with commercial liquid base cytology transport media.

H1: Locally prepared transport media for cytological sample has a significant change with

commercial liquid base cytology transport media.

 CHAPTER TWO

2.0 LITERATURE REVIEW

2.1 Cytology

Cytopathology is commonly used to investigate diseases involving a wide range of body

sites, often to aid in the diagnosis of cancer but also in the diagnosis of some infectious

diseases and other inflammatory conditions (Kirkpatrick, 2022).. For example, a common

application of cytopathology is the Pap smear, a screening tool used to detect precancerous

cervical lesions that may lead to cervical cancer.

Cytopathologic tests are sometimes called smear tests because the samples may be smeared

across a glass microscope slide for subsequent staining and microscopic examination.

However, cytology samples may be prepared in other ways, including cytocentrifugation.

Different types of smear tests may also be used for cancer diagnosis. In this sense, it is

termed a cytologic smear.

2.1.1 Utilization of Cytopathology

The following are the ultimate objectives from utilization of most cytological specimen:

2.1.1.1 The optimum goal is to reach a definitive diagnosis

This objective is the ultimate goal. Clinicians, patients, and pathologists are all interested to

reach a definitive specific diagnosis utilizing single diagnostic test. It is well recognized now

that the utilization of different cytological examinations from different organs provides

sufficient diagnostic information that drives treatment decisions (Caddy et al., 2005;

Kontzoglou et al., 2005).

2.1.1.2 Screening tool

The success story of utilizing Papanicolaou smears in detecting early precursor lesions of

cervical cancer is well known in the developed word. Rates of cancer death due to cervical

cancer dropped tremendously after the 1960s when the Papanicolaou smears screening

programs had started (Taylor et al., 2000; Turkistanli et al., 2003)

2.1.1.3 Follow-up for different diseases

Cytological examinations of specimens taken from different sites as a follow-up after

establishing the initial diagnosis is a routine procedure. Sputum, bronchoalveolar lavage, and

bronchial brushings are frequent samples that are used as follow-up for patients with a

previous diagnosis of pulmonary carcinoma. Additional common samples that can be used

include: pleural fluid, peritoneal fluid, discharge samples, cerebrospinal fluid, and FNA from

any palpable or non-palpable deep-seated new lesions that appear during the follow-up

period.

2.1.2 Advantages of Using Cytology

The advantages of utilizing cytological examination over traditional tissue are well known,

the most important of which are:

2.1.2.1 Safe

The procedures that are used to get cytological samples are extremely safe. Complications are

very rare and when they occur they are relatively mild. Hematomas and pneumothoraces are

among those. The most serious complication that may occur and had been reported is the

development of pneumothorax during FNA of lung lesions. However, less than 5% of those

are serious and require insertion of chest tube (Shantaveerappa et al., 2002; Mullan et al.,

2004). In addition, if the procedure is done under image guidance, immediate evacuation
using the same needle is now recommended and had been successfully achieved. Paying

attention to the risk factors for the development of pneumothorax may decrease their rate.

Hematomas are observed more frequently in patients who have coagulopathies (Rios et al.,

2001). Prevention of such complications is easily achieved by applying gentle pressure for

longer periods after the procedure. It is also recommended to consult with the hematologist in

the institution to prepare those patients who suffer from bleeding disorders or are on

anticoagulation therapy. Pain and patient discomfort are relatively mild and can be prevented

by appropriate preparation of patients and by applying local anesthesia, if necessary.

Infections are extremely rare and can be avoided by following the international safety

guidelines and sterile techniques (Ryan et al., 2002; Lee et al., 2005).

2.1.2.2 Simple

It is well known that getting most cytological samples is simple. With increasing familiarity

of different sampling techniques, currently almost all institutions and health care providers

are aware of the technology and it is part of routine investigative and diagnostic patient work

up. Description of different types of samples will follow.

2.1.2.3 Quick

The procedure is very quick and diagnostic answers can be provided immediately at the time

of procedure, if needed, or within the next 24-48 hours (Kramer and Groen; 2003; Nayek et

al., 2004; Mazza et al., 2005).

2.1.2.4 Cost effective

The cost effectiveness of cytological examination is well documented in the literature, a

feature that is becoming very critical given the current high health care costs. Compared to

surgical biopsies, the amount of savings is substantial (Chaiwun et al., 2002; Nasuti et al.,

2002; Eedes and Wang, 2004).

2.1.3 Branches of Cytopathology

2.1.3.1 Exfoliative cytology

The samples represent cells that exfoliate from superficial or deep serosal or mucosal

surfaces. This includes:

1. Gynecological samples: Papanicolaou smears are the first samples that started the

exponential revolution of the cytopathology field. Recently, almost all health care providers

are moving away from the conventional Papanicolaou smears and moving to what is called

fluid-based technology that can provide more accurate interpretation and allows for

molecular testing for the Human Papilloma Virus (HPV) infection (Yarkin et al., 2003;

Matthews-Greer et al., 2004; Schiller et al., 2004).

2. Respiratory/exfoliative cytology, which includes bronchial washing, sputum,

bronchoalveolar lavage, and bronchial brushing cytology. Those are commonly used to detect

pulmonary infections and malignancies (Mousa and Al-Abbadi, 2011).

3. Urinary cytology: Urine cytology, bladder washing, and brushing cytology. The urinary

cytology field is passing through tremendous research recently. So, in addition to

cytomorphological examination, the utilization of urine samples for detection of common

chromosomal aberrations in urothelial neoplasms has been recently refined. Commercial kits

utilizing the Fluorescent in Situ Hybridization (FISH) are already available and in use

(Sarosdy et al., 2002; Degtyar et al., 2004; Mousa and Al-Abbadi, 2011).

4. Body fluid cytology: Common samples include pleural fluid, pericardial fluid, peritoneal

fluid, and cerebrospinal fluid (CSF) cytology. Similar to respiratory samples, those are also

used mainly to detect malignancies and infections.

5. Gastrointestinal Tract: Sampling the mucosa of the gastrointestinal tract is becoming a

routine procedure during endoscopy. Brushing samples are used to detect viral and fungal

infections, and neoplasia with its precursor lesions.

6. Discharge cytology: Discharge from any anatomic location can be easily examined to

investigate infections and malignancies. The most common sample is breast nipple discharge

that is used as a screening method for detection of mammary carcinoma (Mousa and Al-

Abbadi, 2011).

7. Scrape cytology: This technique is very simple and can be performed by either clinicians

or pathologists at the bedside or in the clinic. Detection of infections and cancer cells at any

surface (skin or mucosa) can be quick and accurate (Mousa and Al-Abbadi, 2011).

2.1.3.2 Aspiration cytology

Different names are used to describe this expanding technique. The most famous ones are

FNA, fine needle aspiration biopsy (FNAB), and needle aspiration biopsy cytology (NABC).

All of them mean the same thing; aspirating cellular material using a fine needle to make a

diagnosis. This technique has been used from any lesion in the body which includes two

major areas:

1. Palpable lesions: Palpable lesions can be targeted by a clinician and preferably by an

experienced cytopathologist. The advantages of having a cytopathologist performing or at

least be available to confirm material adequacy are well studied in the literature.

2. Non-palpable lesions: The non-palpable lesions are usually done with the help of image

analysis (CT scanguided, ultrasound-guided, fluoroscopy-guided, and recently endoscopic

ultrasound-guided fine needle aspiration).

2.1.4 Technical Aspects of Cytology

The initial smears are usually stained by a quick stain (stains, which needs approximately one

minute to perform) such as Diff Quick (DQ) stain, a modified Romanowsky stain.

This type of stain is done on slides with material after airdrying and this is why they are also

called air-dried based stains. The other set of slides are fixed in basic ethanolbased solution

(preferable 95% ethanol) for different type of stain, the Papanicolaou stain. In addition to the

previous smears which are prepared at the time of the fine needle aspiration, the rest of the

material is usually flushed in an ethanol or formalin-based solution after which the material is

centrifuged and a small mini biopsy is created from the concentrated cellular material at the

bottom of the tube; this is known as the cell block. The slides from the cell block are usually

stained by a regular Hematoxylin and Eosin (HandE) stain. These three types of stains are

commonly used in different laboratories. Each one of those has its advantages and

disadvantages (Mousa and Al-Abbadi, 2011). For example, DQ stain is good for

microorganisms, cytoplasm, and background material staining. In the meantime,

Papanicolaou stain is more superior for demonstrating the nuclear details, which are the most

important and specific in making the diagnosis of malignancy. The HandE stain combines the

advantages of both Papanicolaou and DQ stains and gives the pathologist a chance to

evaluate tissue-like stains similar to routine biopsies.

Different types of smear preparations are utilized in the cytopathology laboratory, which

includes:

1. Direct smears as described above.

2. Cytocentrifuge smears, which are prepared using the cytocentrifuge method. This method

concentrates the material and is especially advantageous when few cells are present in a large

amount of fluid, such as pleural or peritoneal fluids (Mousa and Al-Abbadi, 2011).

3. Centrifuge smears using membrane filters. This method utilizes the use of paper filter with

very small pores to trap contaminating material. It is becoming obsolete since the slide

cellular morphology is usually compromised.

4. Monolayer liquid-based cytology. This technology is now the standard method that is used

to prepare Papanicolaou smears. The smears are superior to their conventional counterparts

and also allow testing for Human Papilloma Virus DNA particles (Yarkin et al., 2003;

Matthews-Greer et al., 2004; Schiller et al., 2004). The cells are laid on the slide in a

monolayer fashion and the background is clean

5. The last groups of slides are those prepared using the Cellblock technique, as described

above. Those slides are prepared utilizing formalin-fixed paraffin-embedded tissue. The

availability of such material provides the pathologist with material that can be used to do

special necessary stains. Microorganisms and immunohistochemical stains are the most

commonly used (Rader et al., 2001; Han et al., 2004).

2.1.4.1 Fine Needle Aspiration Technique

There is still no agreed upon standard for the best aspiration technique in cytopathology.

However, all FNA experts agree on one thing, every aspirator have to get comfortable with

one method and modify it as more experience is gained. The bottom line is to get enough

diagnostic cells from the area of interest. The gauges of the needles used vary, however, 21-

25 French gauge needles are the most frequent. Whether to use a gun (syringe holder) or not

when negative pressure is utilized, is left for the level of comfort of the aspirator. Some
believe that using the gun provides more control and more cells (Mousa and Al-Abbadi,

2011). The most common techniques that are used include

1. Aspiration using a fine needle (gauge range 21-25) without negative pressure or a syringe.

This technique is also known as “the French technique” and clinicians, radiologists and

pathologists who use this method believe that it is less traumatic than the others and yield

enough diagnostic cells by the mere capillary pressure.

2. Aspiration using a syringe and needle without negative pressure. This method allows the

aforementioned capillary pressure to push cells in the hub of the needle avoiding the trauma

of negative pressure. It is believed that adding the syringe will allow collection of fluids if the

lesion turned to be cystic.

3. Aspiration using a syringe and needle with utilization of negative pressure. The amount of

negative pressure varies; however, 2-3 cm. of negative pressure in a 10 ml syringe is

commonly used. This is the method that the author uses without a gun and inserting the

needle in a circular way to sample the whole area of the lesion (Mousa and Al-Abbadi, 2011).

2.1.5 Cytological Features of Malignancy

There is no single feature that is diagnostic of malignancy. It is the constellation of multiple

factors that vary depending on the tissue aspirated, the collection technique and the smear

preparation method. It is very important to be aware of these variables before attempting to

make a final cytological diagnosis. The general features of malignancy in cytological slides

are high cellularity, cellular enlargement, increased nuclear/cytoplasmic ratio, nuclear

hyperchromasia, discohesiveness of cells, prominent and large nucleoli, abnormal distribution

of nuclear chromatin, increased mitotic activity and specially the presence of abnormal ones,

nuclear membrane abnormalities, cellular and nuclear pleomorphism, and background tumor
necrosis (also known as tumor diathesis). Ultimately, we are all responsible for providing an

accurate cytological diagnosis.

Problems can arise anytime anywhere from the time the patient is seen until the time the final

report is transcribed and faxed or sent to the clinician. Trouble shooting is very important to

identify problems, which can arise anytime (Mousa and Al-Abbadi, 2011).

2.1.6 Diagnostic Pitfalls

Diagnostic pitfalls can still occur and are usually due to:

1. Poor collection technique: This can occur when the appropriate slides or containers with

appropriate fixatives are not used at the time of the procedure. This can be resolved by

consulting with the pathology/cytopathology department for help (Mousa and Al-Abbadi,

2011).

2. Poor fixation: This is sometimes seen when there is no experience with cytopathology

material preparation and collection. Communication with your pathologist is recommended.

3. Inflammatory changes: As described before, sometime extensive inflammation may

obscure cellular details and prevent appropriate interpretation. To avoid this problem, treating

the patient and repeating the procedure afterwards is recommended.

4. Cellular changes related to radiation and/or chemotherapy: This issue comes up if the

patient had already been diagnosed with malignancy and was treated with chemotherapy

and/or radiation therapy. Certain changes are induced by these treatment modalities. To

decrease the pitfalls from these changes, appropriate and detailed history should be given by

clinicians and awareness of the changes by the pathologist should be taken into consideration.

5. Atypical cellular changes related to hemorrhage, infarction, or necrosis can be problematic.

Awareness of these changes by the cytopathologist is very helpful to prevent both false
positive and false negative diagnosis. Having a pathologist/cytopathologist at the time of the

procedure or performance of the procedure by a pathologist will help alert the pathologist to

these changes (Mousa and Al-Abbadi, 2011).

2.2 Liquid based cytology

Liquid-based cytology is a method of preparing samples for examination in cytopathology.

The sample is collected, normally by a small brush, in the same way as for a conventional

smear test, but rather than the smear being transferred directly to a microscope slide, the

sample is deposited into a small bottle of preservative liquid. At the laboratory, the liquid is

treated to remove other elements such as mucus before a layer of cells is placed on a slide

(Liptak et al., 2012).

For many years, efforts have been made to develop methods that would enhance the

sensitivity and specificity of the Papanicolaou smear (also called Pap History smear).

Emphasis has been placed on creating automated screening machines whose success depends

on a representative sampling of cells on standardized slides containing a monolayer of well-

stained, well-preserved cells (Wilbur et al., 2008).

From this research and development, liquid-based gynecologic specimen collection has

evolved. Its proponents argue that liquid-based preparations outperform conventional smears

because of improved fixation, decreased obscuring factors, and standardization of cell

transfer. Proponents point out that, in direct smears, the cells are not transferred in a

representative fashion and that up to 90% of the material scraped from the cervix may be

discarded with the sampling device. With liquid-based collection, the sampling will be
representative and operator-dependent variation will not occur since processing is controlled

by the laboratory.

Liquid-based cytology (LBC) is a monolayer slide preparation technology that has

outperformed conventional Pap smears because of improved fixation, decreased obscuring

factors, and standardized cell transfer. In LBC, samples are collected by completely

immersing the sampling device into the company vial containing preservative fluid, whereby

the cells are preserved and fixed simultaneously unlike conventional smears where the

sample is smeared onto the glass slide and fixed separately (Manjiri and Prajakta, 2022). To

date, two major liquid-based preparation methods are known – ThinPrep and SurePath. These

two methods are different in their principles of cell harvesting but produce similar

preparations. SurePath works on the principle of density gradient sedimentation. In this, a

sample is vortexed and strained to break the mucus and large cell groups and then is treated

through a density gradient centrifugation process to remove blood and debris. The cell pellet

is resuspended and is allowed to sediment onto a glass slide. This is followed by staining on

the PrepStain instrument (Manjiri and Prajakta, 2022). In LBC, samples are collected by

completely immersing the sampling device into the company vial containing preservative

fluid unlike conventional smears where the sample is smeared on the slide and fixed

separately. The preservative fluid-containing sample is then processed in a laboratory (using

ThinPrep or SurePath) and a smear representing monolayer cell sample with a clean

background is formed.

2.2.1 SurePath

BD SurePath™ works on the principle of density gradient sedimentation. In this, the

cell/sample is vortexed and strained to break the mucus and large cell groups and then is

treated through a density gradient centrifugation process to remove blood and debris. The cell
pellet is resuspended and is allowed to sediment onto a glass slide (Manjiri and Prajakta,

2022).

2.2.2 ThinPrep

Principle

In this procedure, samples are collected in a vial containing a filter and methanol-based

preservative (provided by the company). The vials are placed one at a time on the semi-

automated ThinPrep machine. The filter within the vial rotates mechanically dispersing cells,

mucus, blood, and debris. This suspension of cells is passed through a filter made up of

neutral polycarbonate. The flow of this suspension is constantly monitored to get an optimal

quantity of cells. The cells trapped onto the filter surface are automatically transferred to a

glass slide and fixed immediately (Manjiri and Prajakta, 2022).

 CHAPTER THREE

3.0 MATERIALS AND METHODS

3.1 Study Area

The study was carried out in University of Maiduguri Teaching Hospital (UMTH), Borno

state. Borno State is located in the North Eastern geographical zone of Nigeria. Borno State

is the largest of the six states in North-Eastern Nigeria. The state lies on coordinates 11°30′N

13°00′E. It has a total landmass of 70,898 square kilometres and has a population density of

72 people per square kilometres. It shares borders with the Republics of Niger to the north,

Chad to the north-east and Cameroun to the east. Within Nigeria, Borno State shares

boundaries with Adamawa State to the South, Gombe State to the West and Yobe State to the

north-west. Borno State has an estimated population of 4,171,104 (2,163,358 males and

2,007,746 females). This accounts for 3.0% of Nigeria’s total population (NPC, 2006).
3.3 Sample Collection

The informed consent forms were distributed to the participants recruited for the study after

explaining the type and purpose of the research to them. After obtaining informed consent

from the participants, buccal swabr was collected from the participants.

3.4 Selection Criteria

3.4.1 Inclusion Criteria

Apparently healthy participants were recruited for the study.

Both males and females were used in the study.

3.4.2 Exclusion Criteria

Participants that did not give consent were excluded

3.6 Methodology
3.6.1 Papanicolaou stain

Papanicolaou stain is the most important stain utilized in the practice of cytopathology. It is a

polychromatic stain containing multiple dyes to differentially stain various components of the

cells

3.6.2 Principle

Papanicolaou stain includes both acidic and basic dyes. Acidic dye stains the basic

components of the cell and basic dye stain the acidic components of the cell. The

polychromatic PAP stain involves five dyes;

3.6.2.1 Hematoxylin

Natural dye hematoxylin is the nuclear stain which stains cell nuclei blue. It has affinity for

chromatin, attaching to sulphate groups on the DNA molecule.

3.6.2.2 Orange Green 6

This is the first acidic counterstain (cytoplasmic stain) which stains matured and keratinized

cells. The target structures are stained orange in different intensities.

3.6.2.3 Eosin Azure

This is the second counterstain which is a polychrome mixture of eosin Y, light green SF and

Bismarck brown. Eosin Y gives a pink colour to cytoplasm of mature squamous cells,

nucleoli, cilia and red blood cells.

3.6.2.4 Light green SF

Stains blue to cytoplasm of metabolically active cells like parabasal squamous cells,

intermediate squamous cells and columnar cells.

3.6.2.5 Bismarck brown Y

Stains nothing and sometimes it is often omitted.

3.6.3 Procedure

1. The smear was fixed in 95% ethanol for 15 minutes

2. It was rinsed in tap water

3. The smear was stained with Harris hematoxylin dye for 2 minutes

4. It was rinsed in Scott’s tap water

5. The smear was dipped in 95% ethanol for few seconds

6. The smear was stained with orange G-6 for 2 minutes

7. It was dipped in 95% ethanol for few seconds

8. The smear was stained with eosin for 2 minutes

9. It was dipped in two changes of 95% ethanol for few seconds

10. The smear was dehydrated in 100% for 1 minutes

11. It was cleared in two changes of xylene for 2 minutes each

12 The slide was mounted.

CHAPTER FOUR
4.0 RESULTS
4.1 Analysis of Study Population
This study was designed to evaluate locally prepared verse commercial liquid base cytology

transport media for cytological sample preservation analysis. The results were displayed in

tables and photomicrograph accordingly as shown below.

Table 4.1 shows the socio-demographic data of the participants. Ten (10) study subjects

whose informed consent has been obtained were recruited into the study and it consisted of

6(60%) females and 4(40%) males with a mean age of 29.53±9.79 years.

Five buccal smears were immersed in locally prepared transport media and commercial liquid

base cytology transport media each. The results were displayed in photomicrographs
Table 4.1: Socio-demographic data of study subjects

Variables Study subjects

Age (years) 29.53±9.79

Gender Female 6(60%)

Male 4(40%)
Plate 4.1: Photomicrograph of Pap stained buccal smear after preserving in commercial liquid

based cytology transport media. The picture shows poor cytoplasmic details and background.
Plate 4.2: Photomicrograph of Pap stained cytological buccal smear after preserving in

locally prepared liquid based cytology transport media. The picture shows better cytoplasmic

details and background.

CHAPTER FIVE

5.0 DISCUSSION, CONCLUSION AND RECOMMENDATION

5.1 Discussion

Liquid-based cytology is a method of preparing samples for examination in cytopathology.

The sample is collected, normally by a small brush, in the same way as for a conventional

smear test, but rather than the smear being transferred directly to a microscope slide, the

sample is deposited into a small bottle of preservative liquid. At the laboratory, the liquid is

treated to remove other elements such as mucus before a layer of cells is placed on a slide

(Liptak et al., 2012).

The study aimed at evaluating locally prepared verse commercial liquid base cytology

transport media for cytological sample preservation analysis. The study shows that pap

stained cytological buccal smear had poor cytoplasmic details and background when
preserved in commercial prepared liquid based cytology. The study also revealed that better

cytoplasmic details and background were obtained when buccal smear was preserved in

locally prepared liquid based cytology.

5.2 Conclusion

This study demonstrated that better cytoplasmic details and background was obtained when

pap stained cytological buccal smear was preserved in commercial liquid based cytology

transport media. Locally prepared liquid based cytology transport media can effectively

preserve cytological samples which may provide a valuable and cost-effective tool for

diagnostic cytopathology.

5.3 Recommendation

It is recommended that further research should be carried out using a larger sample size of

buccal samples to determine the efficiency of locally prepared liquid based cytology transport

media.
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